Summary of Work: The lab is studying how ligand-gated ion channels regulate synaptic transmission within the central nervous system (CNS); in the CNS, information is conducted primarily through those channels activated by the major excitatory neurotransmitter (NT) glutamate, and the major inhibitory neurotransmitter GABA. Therefore the regulation of the release of these two Nts, and/or the ligand-gated ion channels which they control, will profoundly affect neuronal activity in the CNS. The hyperstimulation of the glutamate response can induce neuronal cell death, and is linked to several neurodegenerative diseases and neuropathological conditions. Within the hippocampus, a brain region particularly important for higher-order brain processing (e.g., learning and memory), GABA is released directly onto the principal excitatory neurons, thereby inhibiting and regulating their activity. Hippocampal cells that release GABA are classified as inhibitory interneurons, and their activity is regulated by the excitatory NTs serotonin (through activation of the 5-HT3 receptor) and acetylcholine (i.e., nicotinic subtype; nAChR). To study these channels, we use a variety of voltage- clamp techniques to record ion channel activity from neurons in brain slices and in culture, and to record from both native and expressed ion channels in immortalized cell lines and frog eggs. Our current efforts have focused don factors which regulate the influx of Ca2+ into neurons, and how Ca2+-dependent processes in turn regulate the functionof these channels. Our most significant finding, one of major importance for neurobiology, concerns our discovery that 5-HT3 and nACh receptor subunits coassemble to form a novel type of heteromeric ion channel with an enhanced permeability to Ca2+. A second major finding relates to our observation that inhibitory interneurons in the hippocampus contain functional nicotinic responses. As these neurons also contain functional 5-HT3 responses, it is possible that 5-HT3 and nicotinic subunits coassemble in these neurons in vivo, resulting in a channel highly permeable to Ca2+, that in turn regulates neuronal activity and therefore the release of GABA from these neurons. In addition to these observations, we have found that Ca2+ influx through VGCC modulates the function of the 5-HT3 receptor channel, and that the activation of PKC leads to the inhibition of the glutamate receptor channels.